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Abstract

Highly active antiretroviral therapy (HAART) commonly leads to persistent dyslipidemia and insulin resistance that appear likely to confer an increased incidence of cardiovascular disease (CVD). Both protease inhibitors (PIs) and, to a lesser extent, nucleoside analog reverse transcriptase inhibitors (NRTIs) appear to be involved, through direct metabolic effects of PIs and an indirect effect of PI and NRTI-related lipodystrophy. Several studies have found a variable relationship between CVD incidence and HAART, but these studies were not prospective and may not have been adequately powered. A variety of treatment strategies have been evaluated for dyslipidemia and insulin resistance, including lifestyle changes, drugs, and antiretroviral switching, but their relative safety, efficacy and roles are unclear. Although treatment of dyslipidemia and insulin resistance is commonly recommended, it should be remembered that such therapy is likely to be of greater benefit in those with a greater perceived CVD risk (i.e., multiple risk factors) and the lowest risk of HIV disease progression.

INTRODUCTION

Highly active antiretroviral therapy (HAART) has led to significant reductions in HIV morbidity and mortality. HAART is a combination of at least three antiretroviral (ARV) drugs: a protease inhibitor (PI) and/or a nonnucleoside analog reverse transcriptase inhibitor (NNRTI) and one or two nucleoside analog reverse transcriptase inhibitors (NRTI). HAART is not a cure for HIV infection, however, and so currently requires permanent and continuous administration (1). There is an increasing focus on the adverse effects associated with HAART. In addition to numerous relatively acute complications, such as hepatitis, neuropathy, hypersensitivity, and pancreatitis, there is growing concern regarding risk factors for cardiovascular disease (CVD) observed in patients receiving HAART; these include hypercholesterolemia, hypertriglyceridemia, low high-density lipoprotein (HDL) cholesterol, and insulin resistance/type 2 diabetes mellitus (2). As CVD is the commonest cause of death in the developed world (3), even a small increase in CVD risk with HAART may lead to significant changes in morbidity and mortality in HIV-infected adults. For similar reasons, it is difficult to determine conclusively whether HAART leads to an increased incidence of CVD.

This paper outlines recent data relating to the prevalence and pathogenesis of CVD risk factors in HIV-infected adults, as well as various potential treatment options.

CVD RISK FACTORS IN HIV-INFECTED ADULTS

Dyslipidemia

A large number of cross-sectional studies and a smaller number of prospective studies in HIV-infected and uninfected adults have consistently demonstrated an increased prevalence of dyslipidemia associated with HAART (2,4-12). Abnormalities in lipid profiles appear to be relatively stable over time if the HAART regimen is unchanged (4). Most PIs, with the possible exceptions of saquinavir and atazanavir, increase plasma levels of both total and low density lipoprotein (LDL) cholesterol, as well as levels of triglycerides (Table 1)(13-15). Prospective data on high density lipoprotein (HDL) cholesterol plasma levels in patients being treated with PIs alone or PI-based HAART are unclear, perhaps because studies were under-powered to assess this endpoint. As HIV infection per se suppresses HDL cholesterol, it would be reasonable to expect a HAART that suppresses HIV replication would also lead to increases in HDL cholesterol. The only ARV agent shown to raise the HDL cholesterol plasma level (which is the greatest single predictor of CVD risk) in a randomized study is nevirapine administered with two NRTIs, whereas PI-based HAART is associated with stable or declining HDL cholesterol levels over time (16-19). Efavirenz appears to have variable effects on plasma levels of both HDL cholesterol and triglycerides, while significantly increasing total cholesterol levels (20).

The largest study of cardiovascular risk is the Data Collection on Adverse Events of Anti-HIV Drugs (D:A:D) Study; it was initiated in 1999 to determine whether HAART increases the rate of CVD (21). Analysis of baseline data from over 17,000 subjects found that the proportion of patients with dyslipidemia likely to incur increased CVD risk grew as the number of ARV classes in their regimens increased. Additional parameters independently associated with the presence of all forms of dyslipidemia were increasing age and clinically diagnosed lipodystrophy. One of the more novel findings was that NNRTI-based HAART was associated with a lower prevalence of low HDL cholesterol levels than PI-based HAART or no ARV therapy. Other cardiovascular risk factors were also relatively common in the D:A:D cohort, particularly smoking (52%), a positive family history of CVD (12%), and hypertension (8%) (Figure 1).

Diabetes Mellitus and Insulin Resistance

Insulin resistance and type 2 diabetes mellitus are also significantly associated with HAART (2,4-6,8-10,12,22,23). The D:A:D study identified diabetes mellitus in 2.5% of patients, a prevalence probably no greater than in the general population. Like most other studies of HIV-infected adults, D:A:D, however, used only fasting glucose to assess glucose tolerance. Use of the more sensitive oral glucose tolerance test identified diabetes in approximately 8-10% of patients taking PI-based HAART, and impaired glucose tolerance in a further 15% of patients (4,22). These studies, as well as D:A:D, demonstrated that abnormal glucose tolerance was significantly associated with current use of PI therapy (but not PI type or duration) as well as increasing age and the presence of clinically diagnosed lipodystrophy. An association between insulin resistance and lipoatrophy is not surprising, as insulin resistance is typical of congenital lipoatrophy and also of central adiposity (syndrome X) (24).

There are less data regarding the direct effects of PIs on glucose metabolism as compared with lipid metabolism. However, indinavir has been shown to increase insulin resistance in non-HIV-infected adults after a single dose (as do saquinavir and nelfinavir in vitro), whereas nelfinavir and amprenavir have not been found to affect insulin sensitivity in vivo(25,26). NRTIs have not been shown to affect lipid or glucose metabolism directly (although this has not been definitively studied) but NRTIs are strongly associated with insulin resistance in patients with lipoatrophy, even in the absence of PI therapy (5,6). There are no published data on the effects of NNRTIs on glucose metabolism.

Pathogenesis of HAART-Related Dyslipidemia and Insulin Resistance

The pathogenesis of dyslipidemia and insulin resistance in HIV-infected adults receiving HAART is complex (Figure 2). PIs affect multiple metabolic pathways, including those involving sterol regulatory enhancer binding protein type-1 (SREBP-1), GLUT-4 and the proteasome with adverse effects on adipocyte growth, insulin signaling and hepatocyte cholesterol synthesis, respectively (27-29). NRTIs are associated with mitochondrial toxicity, lactic acidemia and lipoatrophy (5,6). As mentioned above, lipoatrophy results in leptin deficiency that enhances insulin resistance. Central fat accumulation may also exacerbate insulin resistance, as is seen in syndrome X. Why only some insulin-resistant individuals become diabetic is unknown, although type 2 diabetes in the general population tends to be associated with both reduced insulin secretion and reduced insulin sensitivity. Age and gender are non-treatment factors that are likely to have additional effects.

Estimating Cardiovascular Risk

What is the estimated risk of CVD in patients receiving HAART? The increase in CVD risk with HAART has been estimated, from available lipid and glycemic data using the Framingham equation, to be 1.4 cardiac events per thousand years of PI-based HAART (30). Importantly, if the Framingham equation does apply in this setting, any risks will also depend on the presence and severity of all cardiac risk factors (smoking, hypertension, left ventricular failure, age, dyslipidemia, diabetes) (31). HIV-uninfected patients who have hypercholesterolemia, hypertriglyceridemia and diabetes are at a fivefold higher risk of CVD than those with none of these risk factors (32). There is no biological reason to suspect that HIV-infected adults will not incur similar CVD risk from similar risk factors as HIV-uninfected adults, provided HIV suppression is effective and AIDS is prevented over an extended period.

The CVD risk associated with HAART can also be estimated by calculating the number of patients that need to be treated with a therapy (i.e. HAART) in order for one additional patient to be harmed by that therapy, i.e., the number treated to harm (NNTH) (31). For example, it has been estimated that a male, 50-year-old smoker who receives PI-based HAART for 10 years has a 13% excess risk of ischemic heart disease (IHD). Therefore, one case of IHD will occur for every 7 patients treated with PI-based HAART (NNTH = 7) (Table 2). The 10-year risk was estimated to be similar or even higher for 50-year-old women who smoke (NNTH = 6).

These risks of developing CVD should of course also be balanced against the risks of not treating HIV-infected patients. This is illustrated by two assessments of the risk of developing AIDS over 3 years with either no treatment or HAART (31,33). Patients with low CD4 cell counts and high plasma viral loads were at considerable risk of developing AIDS in the absence of treatment, but those with CD4 cell counts >350 cells/mm3 did not appear to have derived significant reduction in AIDS risk.

Cardiovascular Disease and HAART

Does this perceived risk translate into increased numbers of CVD cases? Several cohort studies have investigated the effects of HAART on CVD incidence. CVD events that have been evaluated include IHD, myocardial infarction (MI) and carotid intima medial thickness (IMT), a known surrogate marker of CVD. HIV-infected patients, with or without HAART, with greater carotid IMT were more likely to be male, older, smokers and to have hypercholesterolemia (34-36). Neither HIV infection nor PI use was significantly associated with greater IMT but, as PIs increase cholesterol, it would be premature to state that there is no adverse effect of PI-based HAART on IMT.

Clinical outcome data estimating CVD risk in relation to the class of ARV therapy are not conclusive. A retrospective study of 36,766 American HIV-infected veterans followed for up to 8 years found no relationship between the increasing use of PIs, NNRTIs or NRTIs and cardiovascular or cerebrovascular morbidity or mortality (37). A further study indicated that PI usage was not associated with an increased risk of CVD events, although HIV infection itself did appear to be a risk factor (38). In contrast, a French study involving 19,795 men concluded that PI therapy was associated with an increased risk of MI, an effect that was proportional to the duration of PI therapy (39).

Treating Cardiovascular Risk

In the light of the information linking HAART to an increased risk of CVD, the focus is now on developing interventions that reduce this risk. In non-HIV-infected adults, effective strategies are smoking cessation, treatment of hypertension, weight reduction and exercise. The latter two strategies are associated with increasing HDL cholesterol levels and reductions in insulin resistance, total cholesterol and triglyceride levels.

Given the relative risks of AIDS without HAART and of CVD with HAART, factors that would affect a decision to treat dyslipidemia or diabetes would include: their severity; presence of CVD symptoms; HIV disease status; the likelihood that a particular HAART regimen would be long-term; and the presence of other CVD risk factors. Nevertheless, it should be remembered that the efficacy and safety of metabolic interventions designed to prevent CVD cannot be extrapolated at this time from studies of healthy adults. It may be that non-HIV lipodystrophy is a more relevant model, in which lipid-lowering and diabetic therapies tend to be far less effective, likely because of the lipoatrophy and central obesity that underlie these disorders.

In HIV-infected adults, increased exercise can reduce central fat accumulation, but at the expense of increased peripheral fat wasting, and was not found to affect any metabolic parameter (40). No dietary intervention has been evaluated. In a randomized, placebo-controlled study, gemfibrozil resulted in modest reduction in triglyceride plasma levels, but no change in cholesterol levels, and appeared to be safe (41). Fluvastatin and pravastatin produced a significant reduction in cholesterol plasma levels in HIV-infected patients with hypercholesterolemia, but failed to affect triglyceride plasma levels or initiate any change in endothelial reactivity, even though this has been reported in non-HIV-infected patients (42,43). Metformin effectively improves insulin sensitivity and reduces visceral adiposity, without appearing to aggravate lactic acidemia (44).

Since PI therapy appears to incur a higher risk of CVD than NNRTIs or NRTIs, one strategy has been to switch from a PI to either a NNRTI- or NRTI-based therapy. To date, switching to nevirapine or abacavir (or both) leads to reductions in plasma levels of triglycerides and total cholesterol within 4 to 12 weeks (20,45-49). Total cholesterol levels did not fall consistently in patients who were switched to efavirenz-based regimens. While insulin resistance improved in some patients who switched to efavirenz or nevirapine, switching to abacavir has not been well studied, and improvement has not been demonstrated for patients with ongoing lipoatrophy (25,26). It is also unclear whether any lipid or glycemic parameter normalizes after switching from a PI-based regimen. Reported studies have only been conducted over periods of 6 to twelve months and longer follow-up periods may provide more conclusive data and an indication of whether these differences will translate into a differential risk of CVD.

CONCLUSIONS

HAART-associated dyslipidemia and insulin resistance are common and persistent, particularly in PI-treated patients. The pathogenesis of these metabolic abnormalities is not clearly understood but involves direct PI effects, lipodystrophy and non-treatment related factors. These seem likely, but are not proven, to incur an increased risk of CVD.

The most effective strategies for dyslipidemia appear to be PI switching to nevirapine or adding statins to the regimen; the best strategy for diabetes is less clear but may be PI switching or metformin administration. As in other areas of medicine, the risk:benefit ratio of HAART should be assessed prior to initiating and changing treatment regimens and all risk factors for CVD, particularly for IHD, reduced as much and as safely as possible. Any primary prevention for dyslipidemia or diabetes should incur minimal risk (in terms of both side effects and ARV failure) and be targeted to those with greater CVD risk.

REFERENCES

1. US Department of Health and Human Services. Guidelines for the use of antiretroviral agents in HIV-infected adults and adolescents. Available at: http://hivatis.org/trtgdlns.html#Adult. Accessed 11 June 2002.

30. Grunfeld C. Disturbances in lipid metabolism due to HIV infection and its therapy [abstract S3]. Presented at the 6th Conference on Retroviruses and Opportunistic Infections, Chicago, U.S.A., February 1999.

42. Mooser V. Atherosclerosis and hyperlipidaemia in the HAART era [plenary lecture]. Presented at the 3rd International Workshop on Adverse Drug Reactions and Lipodystrophy in HIV, Athens, Greece, October 2001.

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